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Wessel, J.* ; Chu, A.Y.* ; Willems, S.M.* ; Wang, S.* ; Yaghootkar, H.* ; Brody, J.A.* ; Dauriz, M.* ; Hivert, M.F.* ; Raghavan, S.* ; Lipovich, L.* ; Hidalgo, B.* ; Fox, K.* ; Huffman, J.E.* ; An, P.* ; Lu, Y.* ; Rasmussen-Torvik, L.J.* ; Grarup, N.* ; Ehm, M.G.* ; Li, L.* ; Baldridge, A.S.* ; Stancáková, A.* ; Abrol, R.* ; Besse, C.* ; Boland, A.* ; Bork-Jensen, J.* ; Fornage, M.* ; Freitag, D.F.* ; Garcia, M.E.* ; Guo, X.* ; Hara, K.* ; Isaacs, A.* ; Jakobsdottir, J.* ; Lange, L.A.* ; Layton, J.C.* ; Li, M.* ; Hua Zhao, J.* ; Meidtner, K.* ; Morrison, A.C.* ; Nalls, M.A.* ; Peters, M.J.* ; Sabater-Lleal, M.* ; Schurmann, C.* ; Silveira, A.* ; Smith, A.V.* ; Southam, L.* ; Stoiber, M.H.* ; Strawbridge, R.J.* ; Taylor, K.D.* ; Varga, T.V.* ; Allin, K.H.* ; Amin, N.* ; Aponte, J.L.* ; Aung, T.* ; Barbieri, C.* ; Bihlmeyer, N.A.* ; Boehnke, M.* ; Bombieri, C.* ; Bowden, D.W.* ; Burns, S.M.* ; Chen, Y.* ; Chen, Y.D.* ; Cheng, C.Y.* ; Correa, A.* ; Czajkowski, J.* ; Dehghan, A.* ; Ehret, G.B.* ; Eiriksdottir, G.* ; Escher, S.A.* ; Farmaki, A.-E.* ; Frånberg, M.* ; Gambaro, G.* ; Giulianini, F.* ; Goddard, W.A.* ; Goel, A.* ; Gottesman, O.* ; Grove, M.L.* ; Gustafsson, S.* ; Hai, Y.* ; Hallmans, G.* ; Heo, J.* ; Hoffmann, P.* ; Ikram, M.K.* ; Jensen, R.A.* ; Jørgensen, M.E.* ; Jørgensen, T.* ; Karaleftheri, M.* ; Khor, C.C.* ; Kirkpatrick, A.* ; Kraja, A.T.* ; Kuusisto, J.* ; Lange, E.M.* ; Lee, I.T.* ; Lee, W.-J.* ; Leong, A.* ; Liao, J.M.* ; Liu, C.* ; Liu, Y.* ; Lindgren, C.M.* ; Linneberg, A.* ; Malerba, G.* ; Mamakou, V.* ; Marouli, E.* ; Maruthur, N.M.* ; Matchan, A.* ; McKean-Cowdin, R.* ; McLeod, O.* ; Metcalf, G.A.* ; Mohlke, K.L.* ; Muzny, D.M.* ; Ntalla, I.* ; Palmer, N.D.* ; Pasko, D.* ; Peter, A.* ; Rayner, N.W.* ; Renström, F.* ; Rice, K.* ; Sala, C.F.* ; Sennblad, B.* ; Serafetinidis, I.* ; Smith, J.A.* ; Soranzo, N.* ; Speliotes, E.K.* ; Stahl, E.A.* ; Stirrups, K.* ; Tentolouris, N.* ; Thanopoulou, A.* ; Torres, M.* ; Traglia, M.* ; Tsafantakis, E.* ; Javad, S.* ; Yanek, L.R.* ; Zengini, E.* ; Becker, D.M.* ; Bis, J.C.* ; Brown, J.B.* ; Cupples, L.A.* ; Hansen, T.* ; Ingelsson, E.* ; Karter, A.J.* ; Lorenzo, C.* ; Mathias, R.A.* ; Norris, J.M.* ; Peloso, G.M.* ; Sheu, W.H.* ; Toniolo, D.* ; Vaidya, D.* ; Varma, R.* ; Wagenknecht, L.E.* ; Boeing, H.* ; Bottinger, E.P.* ; Dedoussis, G.* ; Deloukas, P.* ; Ferrannini, E.* ; Franco, O.H.* ; Franks, P.W.* ; Gibbs, R.A.* ; Gudnason, V.* ; Hamsten, A.* ; Harris, T.B.* ; Hattersley, A.T.* ; Hayward, C.* ; Hofman, A.* ; Jansson, J.H.* ; Langenberg, C.* ; Launer, L.J.* ; Levy, D.* ; Oostra, B.A.* ; O'Donnell, C.J.* ; O'Rahilly, S.* ; Padmanabhan, S.* ; Pankow, J.S.* ; Polasek, O.* ; Province, M.A.* ; Rich, S.S.* ; Ridker, P.M.* ; Rudan, I.* ; Schulze, M.B.* ; Smith, B.H.* ; Uitterlinden, A.G.* ; Walker, M.* ; Watkins, H.* ; Wong, T.Y.* ; Zeggini, E. ; Laakso, M.* ; Borecki, I.B.* ; Chasman, D.I.* ; Pedersen, O.* ; Psaty, B.M.* ; Tai, E.S.* ; van Duijn, C.M.* ; Wareham, N.J.* ; Waterworth, D.M.* ; Boerwinkle, E.* ; Kao, W.H.* ; Florez, J.C* ; Loos, R.J.* ; Wilson, J.G.* ; Frayling, T.M.* ; Siscovick, D.S.* ; Dupuis, J.* ; Rotter, J.I.* ; Meigs, J.B.* ; Scott, R.A.* ; Goodarzi, M.O.*

Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility.

Nat. Commun. 6:5897 (2015)

DOI

Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.

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Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF = 1.4%) with lower FG (beta = -0.09 +/- 0.01 mmol l(-1), P = 3.4 x 10(-12)), T2D risk (OR[95% CI] = 0.86[0.76-0.96], P = 0.010), early insulin secretion (beta = -0.07 +/- 0.035 pmol(insulin) mmol(glucose)(-1), P = 0.048), but higher 2-h glucose (beta = 0.16 +/- 0.05 mmol l(-1), P = 4.3 x 10(-4)). We identify a gene-based association with FG at G6PC2 (p(SKAT) = 6.8 x 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF = 20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (beta = 0.02 +/- 0.004 mmol l(-1), P = 1.3 x 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

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